Aminoheterocyclic compounds with antithrombotic/anticoagulant effect

ABSTRACT

The invention relates to compounds of formula (I), and pharmaceutically-acceptable salts thereof, which possess antithrombotic and anticoagulant properties; processes for preparing compounds of formula (I) and pharmaceutical compositions.

The invention relates to a group of aminoheterocyclic derivatives, andpharmaceutically-acceptable salts thereof, which possess antithromboticand anticoagulant properties and are accordingly useful in methods oftreatment of the human or animal body. The invention also relates toprocesses for the preparation of said aminoheterocyclic derivatives, topharmaceutical compositions containing them and to their use in themanufacture of medicaments for use in the production of anantithrombotic or anticoagulant effect.

The antithrombotic and anticoagulant effect produced by the compounds ofthe invention is believed to be attributable to their strong inhibitoryeffect against the activated coagulation protease known as Factor Xa.Factor Xa is one of a cascade of proteases involved in the complexprocess of blood coagulation. The protease known as thrombin is thefinal protease in the cascade and Factor Xa is the preceding proteasewhich cleaves prothrombin to generate thrombin.

Certain compounds are known to possess Factor Xa inhibitory propertiesand the field has been reviewed by R. B. Wallis, Current Opinion inTherapeutic Patents, 1993, 1173-1179. Thus it is known that twoproteins, one known as antistasin and the other known as tickanticoagulant protein (TAP), are specific Factor Xa inhibitors whichpossess antithrombotic properties in various animal models of thromboticdisease.

It is also known that certain non-peptidic compounds possess Factor Xainhibitory properties. Of the low molecular weight inhibitors mentionedin the review by R. B. Wallis, all possessed a strongly basic group suchas an amidinophenyl or amidinonaphthyl group.

It is the object of the present invention to provide a new class ofagent which lacks the amidino group previously believed to be anessential feature for a Factor Xa inhibitor.

We have now found that certain amino-substituted heterocyclicderivatives possess Factor Xa inhibitory activity and in particular alsopossess the advantage of being selective Factor Xa inhibitors, that isthe enzyme Factor Xa is inhibited strongly at concentrations of testcompound which do not inhibit or which inhibit to a lesser extent theenzyme thrombin which is also a member of the blood coagulationenzymatic cascade.

The compounds of the present invention possess activity in the treatmentor prevention of a variety of medical disorders where anticoagulanttherapy is indicated, for example in the treatment or prevention ofthrombotic events associated with coronary artery and cerebro-vasculardisease. Further examples of such medical disorders include variouscardiovascular and cerebrovascular conditions such as myocardialinfarction, the formation of atherosclerotic plaques, venous or arterialthrombosis, coagulation syndromes, disseminated intravascularcoagulation, vascular injury including reocclusion and restenosisfollowing angioplasty and coronary artery bypass surgery, thrombusformation after the application of blood vessel operative techniques orafter general surgery such as hip replacement surgery, the introductionof artificial heart valves or on the recirculation of blood, cerebralinfarction, cerebral thrombosis, stroke, cerebral embolism, pulmonaryembolism, ischaemia and angina (including unstable angina).

The compounds of the invention are also useful as inhibitors of bloodcoagulation in an ex-vivo situation such as, for example, the storage ofwhole blood or other biological samples suspected to contain Factor Xaand in which coagulation is detrimental.

According to one aspect of the invention there is provided anaminoheterocyclic derivative of formula I, ##STR1## wherein G¹ and G²independently represent CH or N; m is 0, 1 or 2;

R¹ is halogeno, trifluoromethyl, trifluoromethoxy, cyano, NR⁵ R⁶,hydroxy, nitro, (1-4C)alkyl or (1-4C)alkoxy;

T¹ is CH or N;

L¹ is (1-4C)alkylene, (3-6C)cycloalkane-1,2-diyl or(1-3C)alkylene-carbonyl;

R² is hydrogen or (1-4C)alkyl and R³ is hydrogen or (1-4C)alkyl, or R²and R³ together form a (1-4C)alkylene or methylenecarbonyl group,

wherein 1 or 2 methylene groups within L¹ or the ring formed when R² andR³ are linked optionally bears 1 or 2 substituents selected fromcarboxy, CONR⁵ R⁶, (1-4C)alkyl, (1-4C)alkoxycarbonyl,pyrrolidin-1-ylcarbonyl, piperidinocarbonyl, morpholinocarbonyl,piperazin-1-ylcarbonyl, 4-(1-4C)alkylpiperazin-1-ylcarbonyl,hydroxy-(1-4C)alkyl, (1-4C)alkoxy-(1-4C)alkyl, carboxy(1-4C)alkyl,(1-4C)alkylcarbonyl-(1-4C)alkyl, CONR⁵ R⁶ (1-4C)alkyl,pyrrolidin-1-ylcarbonyl-(1-4C)alkyl, piperidino-(1-4C)alkyl,morpholino-(1-4C)alkyl, piperazin-1-yl-(1-4C)alkyl and4-(1-4C)alkylpiperazin-1-yl-(1-4C)alkyl, and wherein any heterocyclicgroup in said substituent optionally bears 1 or 2 (1-4C)alkylsubstituents;

R⁴ is CONR⁷ (CH₂)_(n) S(O)_(p) R⁸, CONH(CH₂)_(q) NR⁹ R¹⁰, or the group(1-4C)alkyl-Y¹ ;

wherein n represents an integer 0 to 4;

p represents 0, 1 or 2;

q represents an integer 2 to 4;

R⁷ represents hydrogen;

R⁸ represents (1-4C)alkyl, phenyl or (1-4C)alkylphenyl, or R⁷ and R⁸together form a (1-4C)alkylene group;

R⁹ and R¹⁰ independently represent hydrogen, (14C)alkyl, phenyl,(1-4C)alkylphenyl, S(O)_(p) R⁸, COR¹¹ or a 5- or 6-membered monocyclicheteroaryl ring containing up to 3 heteroatoms selected from nitrogen,oxygen and sulphur;

R¹¹ represents hydrogen, (1-4C)alkyl, phenyl or (1-4C)alkylphenyl;

Y¹ represents S(O)_(p) R⁸, NHS(O)₂ R⁸, NHCOR¹², O(CH₂)_(r) R¹³,pyrrolidin-1-yl, piperidino, morpholino, thiamorpholino,1-oxothiamorpholino, 1,1-dioxothiamorpholino or piperazin-1yl,

R¹² represents (1-4C)alkyl, phenyl or (1-4C)alkylphenyl;

r represents an integer 1 to 4;

when r represents an integer 2 to 4, R¹³ represents hydroxy,(1-4C)alkoxy, carboxy, (1-4C)alkoxycarbonyl, S(O)_(p) R⁸ or NR⁵ R⁶ ; andwhen r represents 1, R¹³ represents carboxy or (1-4C)alkoxycarbonyl;

wherein any heterocyclic group within R⁴ optionally bears 1 or 2substituents selected from carboxy, CONR⁵ R⁶, (1-4C)alkyl and(1-4C)alkoxycarbonyl, and any phenyl group within R⁴ optionally bears 1or 2 substituents selected from halogeno, trifluoromethyl, cyano,(1-4C)alkyl and (1-4C)alkoxy;

X¹ is a group of the formula O, S(O)_(p), CO, COO, CONR¹⁴ or CR¹⁵ R¹⁶ ;

R⁵, R⁶, R¹⁴, R¹⁵ and R¹⁶ independently represent hydrogen or(1-4C)alkyl; and

Q represents phenyl, naphthyl, phenyl-(1-4C)alkyl or a heterocyclicmoiety containing up to 4 heteroatoms selected from nitrogen, oxygen andsulphur, and Q optionally bears 1, 2 or 3 substituents selected fromhalogeno, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, NR⁵ R⁶,nitro, trifluoromethanesulphonyl, carboxy, CONR⁵ R⁶, (1-4C)alkyl,(1-4C)alkoxy, (1-4C)alkylS(O)_(p), (1-4C)alkoxycarbonyl, (2-4C)alkanoyl,(2-4C)alkanoylamino, hydroxy-(1-4C)alkyl, (1-4C)alkoxy-(1-4C)alkyl,carboxy-(1-4C)alkyl, (1-4C)alkoxycarbonyl-(1-4C) alkyl, CONR⁵ R⁶(1-4C)alkyl, phenyl, heteroaryl, phenoxy, phenylS(O)_(p), benzyl,benzoyl, heteroaryloxy, heteroarylS(O)_(p), wherein saidheteroaryl-containing substituent comprises a 5- or 6-memberedmonocyclic heteroaryl ring containing up to 3 heteroatoms selected fromnitrogen, oxygen and sulphur, and wherein said phenyl, heteroaryl,phenoxy, phenylS(O)_(p), heteroaryloxy, heteroarylS(O)_(p), benzyl orbenzoyl substituent optionally bears 1, 2 or 3 substituents selectedfrom halogeno, trifluoromethyl, cyano, hydroxy, NR⁵ R⁶, nitro, carboxy,CONR⁵ R⁶, (1-4C)alkyl, (1-4C)alkoxy, (1-4C)alkoxycarbonyl and(2-4C)alkanoylamino;

or a phamaceutically-acceptable salt thereof.

In this specification the term "alkyl" includes both straight andbranched chain, saturated and unsaturated alkyl groups but references toindividual alkyl groups such as "propyl" are specific for the straightchain version only. An analogous convention applies to other genericterms.

It is to be understood that certain aminoheterocyclic derivatives of thepresent invention can exist in solvated as well as unsolvated forms suchas, for example, hydrated forms. It is to be understood that theinvention encompasses all such solvated forms which possess Factor Xainhibitory activity.

It is further to be understood that, insofar as certain of the compoundsof the formula defined above may exist in optically active or racemicforms by virtue of one or more asymmetric carbon atoms, the inventionencompasses any such optically active or racemic form which possessesFactor Xa inhibitory activity. The synthesis of optically active formsmay be carried out by standard techniques of organic chemistry wellknown in the art, for example by synthesis from optically activestarting materials or by resolution of a racemic form.

Suitable values for the generic terms referred to above include thoseset out below.

When m is 2, each R¹ is independently selected from the list ofsubstituents defined hereinbefore.

A suitable value for R¹ when it is a halogeno group or for a halogenosubstituent on a phenyl group within the definition of R⁴, on Q or on aphenyl- or heteroaryl-containing substituent on Q is, for example,fluoro, chloro, bromo or iodo.

A suitable value for R¹ when it is a (1-4C)alkyl group or for a(1-4C)alkyl substituent on a heterocyclic or phenyl group within thedefinition of R⁴, on Q or on a phenyl- or heteroaryl-containingsubstituent on Q is, for example, methyl, ethyl, propyl, isopropyl,butyl, isobutyl, sec-butyl or tert-butyl.

A suitable value for R¹ when it is a (1-4C)alkoxy group or for a(1-4C)alkoxy substituent on a phenyl group within the definition of R⁴,on Q or on a phenyl- or heteroaryl-containing substituent on Q is, forexample, methoxy, ethoxy, propoxy, isopropoxy or butoxy.

A suitable value for R¹ when it is a (1-4C) alkylamino group or for a(1-4C)alkylamino substituent on Q or on a phenyl- orheteroaryl-containing substituent on Q is, for example, methylamino,ethylamino or propylamino.

A suitable value for R¹ when it is di-(1-4C)alkylamino or for adi-(1-4C)alkylamino substituent on Q or on a phenyl- orheteroaryl-containing substituent on Q is, for example, dimethylamino,N-ethyl-N-methylamino or diethylamino.

A suitable value for R², R³, R⁵, R⁶ or any one of R⁸ to R¹⁶ when it is(1-4C)alkyl is, for example, methyl, ethyl, propyl, isopropyl, butyl orsec-butyl.

A suitable value for a (1-4C)alkylene group formed by R² and R³ togetheris, for example, methylene, ethylene, trimethylene or tetramethylene.

A suitable value for L¹ when it is (1-4C)alkylene is, for example,methylene, ethylene, trimethylene or tetramethylene; when it is(3-6C)cycloalkane-1,2-diyl is, for example, cyclopropane-1,2-diyl,cyclobutane-1,2-diyl, cyclopentane-1,2-diyl or cyclohexane-1,2-diyl; andwhen it is (1-3C)alkylene-carbonyl is, for example, methylenecarbonyl,ethylenecarbonyl or trimethylenecarbonyl.

A suitable value for a substituent which may be present on 1 or 2methylene groups within L¹ or the ring formed when R² and R³ are linkedis, for example, as follows:

    ______________________________________                                        for (1-4C)alkyl:                                                                             methyl, ethyl and propyl;                                      for (1-4C)alkoxycarbonyl:                                                                    methoxycarbonyl, ethoxycarbonyl,                                              propoxycarbonyl and tert-butoxycarbonyl;                       for N-(1-4C)alkylcarbamoyl:                                                                  N-methylcarbamoyl, N-ethylcarbamoyl                                           and N-propylcarbamoyl;                                         for N,N-di-[(1-4C)alkyl]-                                                                    N,N-dimethylcarbamoyl,                                         carbamoyl:     N-ethyl-N-methylcarbamoyl and                                                 N,N-diethylcarbamoyl;                                          for 4-(1-4C)alkylpiperazin-                                                                  4-methylpiperazin-1-ylcarbonyl and                             1-ylcarbonyl:  4-ethylpiperazin-1-ylcarbonyl;                                 for hydroxy-(1-4C)alkyl:                                                                     hydroxymethyl, 1-hydroxyethyl,                                                2-hydroxyethyl and 3-hydroxypropyl;                            for (1-4C)alkoxy-                                                                            methoxymethyl, ethoxymethyl,                                   (1-4C)alkyl:   1-methoxymethyl,2-methoxyethyl,                                               2-ethoxyethyl and 3-methoxypropyl;                             for carboxy-(1-4C)alkyl:                                                                     carboxymethyl, 1-carboxyethyl,                                                2-carboxyethyl and 3-carboxypropyl;                            for (1-4C)alkoxycarbonyl-                                                                    methoxycarbonylmethyl,                                         (1-4C)alkyl:   ethoxycarbonylmethyl, tert-butoxy-                                            carbonylmethyl, 1-methoxycarbonylethyl,                                       1-ethoxycarbonylethyl,                                                        2-methoxycarbonylethyl,                                                       2-ethoxycarbonylethyl,                                                        3-methoxycarbonylpropyl and                                                   3-ethoxycarbonylpropyl;                                        for carbamoyl-(1-4C)alkyl:                                                                   carbamoylmethyl, 1-carbamoylethyl,                                            2-carbamoylethyl and                                                          3-carbamoylpropyl;                                             for N-(1-4C)alkylcarbamoyl-                                                                  N-methylcarbamoylmethyl,                                       (1-4C)alkyl:   N-ethylcarbamoylmethyl,                                                       N-propylcarbamoylmethyl,                                                      1-(N-methylcarbamoyl)ethyl,                                                   1-(N-ethylcarbamoyl)ethyl,                                                    2-(N-methylcarbamoyl)ethyl,                                                   2-(N-ethylcarbamoyl)ethyl and                                                 3-(N-methylcarbamoyl)propyl;                                   for N,N-di-[(1-4C)alkyl]-                                                                    N,N-dimethylcarbamoylmethyl,                                   carbamoyl-(1-4C)alkyl:                                                                       N-ethyl-N-methylcarbamoylmethyl,                                              N,N-diethylcarbamoylmethyl,                                                   1-(N,N-dimethylcarbamoyl)ethyl,                                               1-(N,N-diethylcarbamoyl)ethyl,                                                2-(N,N-dimethylcarbamoyl)ethyl,                                               2-(N,N-diethylcarbamoyl)ethyl and                                             3-(N,N-dimethylcarbamoyl)propyl;                               for pyrrolidin-1-ylcarbonyl-                                                                 pyrrolidin-1-ylcarbonylmethyl,                                 (1-4C)alkyl:   1-(pyrrolidin-1-ylcarbonyl)ethyl and                                          2-(pyrrolidin-1-ylcarbonyl)ethyl;                              for piperidinocarbonyl-                                                                      piperidinocarbonylmethyl,                                      (1-4C)alkyl:   1-(piperidinocarbonyl)ethyl and                                               2-(piperidinocarbonyl)ethyl;                                   for morpholinocarbonyl-                                                                      morpholinocarbonylmethyl,                                      (1-4C)alkyl:   1-(morpholinocarbonyl)ethyl and                                               2-(morpholinocarbonyl)ethyl;                                   for piperazin-1-ylcarbonyl-                                                                  piperazin-1-ylcarbonylmethyl,                                  (1-4C)alkyl:   1-(piperazin-1-ylcarbonyl)ethyl and                                           2-(piperazin-1-ylcarbonyl)ethyl;                               for 4-(1-4C)alkylpiperazin-                                                                  4-methylpiperazin-1-ylcarbonylmethyl,                          1-ylcarbonyl-(1-4C)alkyl:                                                                    4-ethylpiperazin-1-ylcarbonylmethyl,                                          2-(4-methylpiperazin-1-ylcarbonyl)                                            ethyl and 2-(4-ethylpiperazin-1-                                              ylcarbonyl)ethyl.                                              ______________________________________                                    

A suitable value for a (1-4C)alkyl group which may be present on aheterocyclic group in a substituent on L¹ or the ring formed when R² andR³ are linked is, for example, methyl, ethyl or propyl.

Suitable values for substituents which may be present on a heterocyclicor phenyl group within the definition of R⁴, on Q or on a phenyl- orheteroaryl-containing substituent on Q include, for example:

    ______________________________________                                        for (2-4C)alkenyl:                                                                           vinyl and allyl;                                               for (2-4C)alkynyl:                                                                           ethynyl and prop-2-ynyl;                                       for (2-4C)alkenyloxy:                                                                        vinyloxy and allyloxy;                                         for (2-4C)alkynyloxy:                                                                        ethynyloxy and prop-2-ynyloxy;                                 for (1-4C)alkylthio:                                                                         methylthio, ethylthio and propylthio;                          for (1-4C)alkylsulphinyl:                                                                    methylsulphinyl, ethylsulphinyl and                                           propylsulphinyl;                                               for (1-4C)alkylsulphonyl:                                                                    methylsulphonyl, ethylsulphonyl and                                           propylsulphonyl;                                               for (2-4C)alkanoylamino:                                                                     acetamido, propionamido and butyramido;                        for (1-4C)alkoxycarbonyl:                                                                    methoxycarbonyl, ethoxycarbonyl,                                              propoxycarbonyl and tert-butoxycarbonyl;                       for N-(1-4C)alkylcarbamoyl:                                                                  N-methylcarbamoyl, N-ethylcarbamoyl                                           and N-propylcarbamoyl;                                         for N,N-di-[(1-4C)alkyl]-                                                                    N,N-dimethylcarbamoyl,                                         carbamoyl:     N-ethyl-N-methylcarbamoyl and                                                 N,N-diethylcarbamoyl;                                          for (2-4C)alkanoyl:                                                                          acetyl, propionyl and butyryl;                                 for hydroxy-(1-4C)alkyl:                                                                     hydroxymethyl, 1-hydroxyethyl,                                                2-hydroxyethyl and 3-hydroxypropyl;                            for (1-4C)alkoxy-                                                                            methoxymethyl, ethoxymethyl,                                   (1-4C)alkyl:   1-methoxymethyl, 2-methoxyethyl,                                              2-ethoxyethyl and 3-methoxypropyl,                             for carboxy-(1-4C)alkyl:                                                                     carboxymethyl, 1-carboxyethyl,                                                2-carboxyethyl and 3-carboxypropyl;                            for (1-4C)alkoxycarbonyl-                                                                    methoxycarbonylmethyl,                                         (1-4C)alkyl:   ethoxycarbonylmethyl, tert-butoxy-                                            carbonylmethyl, 1-methoxycarbonylethyl,                                       1-ethoxycarbonylethyl,                                                        2-methoxycarbonylethyl,                                                       2-ethoxycarbonylethyl,                                                        3-methoxycarbonylpropyl and                                                   3-ethoxycarbonylpropyl;                                        for carbamoyl-(1-4C)alkyl:                                                                   carbamoylmethyl, 1-carbamoylethyl,                                            2-carbamoylethyl and 3-carbamoylpropyl;                        for N-(1-4C)alkylcarbamoyl-                                                                  N-methylcarbamoylmethyl,                                       (1-4C)alkyl:   N-ethylcarbamoylmethyl,                                                       N-propylcarbamoylmethyl,                                                      1-(N-methylcarbamoyl)ethyl,                                                   1-(N-ethylcarbamoyl)ethyl,                                                    2-(N-methylcarbamoyl)ethyl,                                                   2-(N-ethylcarbamoyl)ethyl and                                                 3-(N-methylcarbamoyl)propyl;                                   for N,N-di-[(1-4C)alkyl]-                                                                    N,N-dimethylcarbamoylmethyl,                                   carbamoyl-(1-4C)alkyl:                                                                       N-ethyl-N-methylcarbamoylmethyl,                                              N,N-diethylcarbamoylmethyl,                                                   1-(N,N-dimethylcarbamoyl)ethyl,                                               1-(N,N-diethylcarbamoyl)ethyl,                                                2-(N,N-dimethylcarbamoyl)ethyl,                                               2-(N,N-diethylcarbamoyl)ethyl and                                             3-(N,N-dimethylcarbamoyl)propyl;                               ______________________________________                                    

A suitable value for Q when it is naphthyl is, for example, 1-naphthylor 2-naphthyl; when it is phenyl-(1-4C)alkyl is, for example, benzyl,phenethyl and 3-phenylpropyl, when it is phenyl-(2-4C)alkenyl is, forexample, styryl, cinnamyl or 3-phenylprop-2-enyl; and when it isphenyl-(2-4C)alkynyl is, for example, 2-phenylethynyl,3-phenylprop-2-ynyl and 3-phenylprop-1-ynyl.

A suitable value for Q when it is a heterocyclic moiety containing up to4 heteroatoms selected from nitrogen, oxygen and sulphur is, forexample, a 5- or 6-membered heterocyclic moiety which is a single ringor is fused to one or two benzo rings such as furyl, benzofuranyl,tetrahydrofuryl, chromanyl, thienyl, benzothienyl, pyridyl, piperidinyl,quinolyl, 1,2,3,4-tetrahydroquinolinyl, isoquinolyl,1,2,3,4-tetrahydroisoquinolinyl, pyrazinyl, piperazinyl, pyrimidinyl,pyridazinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pyrrolyl,pyrrolidinyl, indolyl, indolinyl, imidazolyl, benzimidazolyl, pyrazolyl,indazolyl, oxazolyl, benzoxazolyl, isoxazolyl, thiazolyl,benzothiazolyl, isothiazolyl, morpholinyl, 4H-1,4-benzoxazinyl,4H-1,4-benzothiazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, oxadiazolyl,furazanyl, thiadiazolyl, tetrazolyl, dibenzofuranyl and dibenzothienyl,which may be attached through any available position including, for anappropriate X¹ group such as, for example, SO₂, CR¹⁵ R¹⁶ or CO, throughany available nitrogen atom and which may bear up to three substituentsincluding a substituent on any available nitrogen atom.

A suitable value for the heteroaryl substituent on Q or the heteroarylgroup in a heteroaryl-containing substituent on Q which comprises a 5-or 6-membered monocyclic heteroaryl ring containing up to 3 heteroatomsselected from oxygen, nitrogen and sulphur is, for example, furyl,thienyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazanyl, pyrrolyl,imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl,1,2,3-triazolyl, 1,2,4-triazolyl, oxadiazolyl, furazanyl andthiadiazolyl which may be attached through any available positionincluding through any available nitrogen atom.

For the avoidance of any doubt it is to be understood that, in theportion of the structure of formula I which has the formula --N(R²)--L¹--T¹ (R³)--X¹, it is the N atom which is attached to L¹ and it is the T¹group which is attached to the CO i.e. neither of the R² and R³ groupsare attached to L¹.

It is further to be understood that, within the structure of formula I,when R² and R³ together form a methylenecarbonyl group, it is themethylene group thereof which is attached to the N atom and the carbonylgroup thereof which is attached to T¹. Similarly when L¹ is a(1-3C)alkylene-carbonyl group, for example a methylenecarbonyl group, itis the methylene group thereof which is attached to the N atom and thecarbonyl group thereof which is attached to T¹.

A suitable pharmaceutically-acceptable salt of an aminoheterocyclicderivative of formula I is, for example, an acid-addition salt of anaminoheterocyclic derivative of formula I which is sufficiently basic,for example, an acid-addition salt with, for example, an inorganic ororganic acid, for example hydrochloric, hydrobromic, sulphuric,phosphoric, trifluoroacetic, citric or maleic acid. In addition asuitable pharmaceutically-acceptable salt of an aminoheterocyclicderivative of formula I which is sufficiently acidic is an alkali metalsalt, for example a sodium or potassium salt, an alkaline earth metalsalt, for example a calcium or magnesium salt, an ammonium salt or asalt with an organic base which affords a physiologically-acceptablecation, for example a salt with methylamine, dimethylamine,trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine.

Particular compounds of the invention include, for example,aminoheterocyclic derivatives of formula I, orpharmaceutically-acceptable salts thereof, wherein, unless otherwisestated, each of G¹, G², m, R¹, R², R³, R⁴, L¹, T¹, X¹ and Q has any ofthe meanings defined hereinbefore or in this section concerningparticular compounds of the invention:

(a) each of G¹ and G² is CH;

(b) G¹ is CH and G² is N, or G¹ is N and G₂ is CH;

(c) m is 0;

(d) L¹ is (1-4C)alkylene, T¹ is CH or N, and R² and R³ together form a(1-4C)alkylene group, and wherein 1 or 2 methylene groups within L¹ andthe ring formed when R² and R³ are linked optionally bears 1 or 2(1-4C)alkyl substituents;

(e) L¹ is ethylene, T¹ is CH, and R² and R³ together form a methylene orethylene group;

(f) L¹ is ethylene, T¹ is CH or N, and R² and R³ together form anethylene group;

(g) L¹ is ethylene, T¹ is CH, and R² and R³ together form an ethylenegroup;

(h) R⁴ is a group of formula CONR⁷ (CH₂)_(n) S(O)_(p) R⁸ orCONH(CH₂)_(q) NR⁹ R¹⁰ ;

(i) X¹ is a group of the formula S(O)_(p) ;

(j) X¹ is a group of the formula SO₂ ;

(k) Q is phenyl, naphthyl or phenyl-(1-4C)alkyl which optionally bears1, 2 or 3 substituents selected from hydroxy, halogeno, cyano,trifluoromethyl, (1-4C)alkyl, (1-4C)alkoxy, phenyl, phenoxy,phenylS(O)_(p), benzyl and benzoyl, and wherein the phenyl substituentor the phenyl group in a phenyl-containing substituent optionally bears1 or 2 substituents selected from halogeno, (1-4C)alkyl and(1-4C)alkoxy;

(1) Q is phenyl which bears a phenyl substituent and optionally bears 1or 2 substituents selected from hydroxy, halogeno, cyano,trifluoromethyl, (1-4C)alkyl and (1-4C)alkoxy, and wherein the phenylsubstituent optionally bears up to 3 substituents selected fromhalogeno, trifluoromethyl, cyano, (1-4C) alkyl and (1-4C)alkoxy;

(m) Q is phenyl-(1-4C) alkyl, phenyl-(2-4C)alkenyl orphenyl-(2-4C)alkynyl which optionally bears 1, 2 or 3 substituentsselected from halogeno, cyano, trifluoromethyl, (1-4C)alkyl and(1-4C)alkoxy;

(n) Q is phenyl-(2-4C)alkenyl which optionally bears 1,2 or 3substituents selected from halogeno, cyano, trifluoromethyl, (1-4C)alkyland (1-4C)alkoxy;

(o) Q is phenyl or phenyl-(1 -4C)alkyl which bears 1 substituentselected from heteroaryl, heteroaryloxy, heteroarylthio,heteroarylsulphinyl and heteroarylsulphonyl, wherein the heteroarylsubstituent or the heteroaryl group in a heteroaryl-containingsubstituent comprises a 5- or 6-membered monocyclic heteroaryl ringcontaining up to 3 heteroatoms selected from nitrogen, oxygen andsulphur, and wherein said heteroaryl or heteroaryl-containingsubstituent optionally bears 1 or 2 substituents selected from halogeno,(1-4C)alkyl and (1-4C)alkoxy;

(p) Q is phenyl which bears 1 substituent selected from heteroaryl,heteroaryloxy, heteroarylthio and heteroarylsulphonyl, wherein theheteroaryl substituent or the heteroaryl group in aheteroaryl-containing substituent is selected from thienyl, pyridyl,pyrimidinyl, pyrazolyl, oxazolyl, thiazolyl, 1,2,3-triazolyl and1,2,4-triazolyl, and wherein said heteroaryl or heteroaryl-containingsubstituent optionally bears 1 or 2 substituents selected from halogenoand (1-4C)alkyl;

(q) Q is naphthyl which optionally bears 1 or 2 substituents selectedfrom hydroxy, halogeno, cyano, trifluoromethyl, (1-4C) alkyl and(1-4C)alkoxy;

(r) Q is a heterocyclic moiety containing up to 2 heteroatoms selectedfrom benzofuranyl, quinolyl, tetrahydroquinolyl, isoquinolyl,quinoxalinyl, quinazolinyl, cinnolinyl, indolyl, benzimidazolyl,indazolyl, benzoxazolyl and benzothiazolyl, and Q optionally bears 1 or2 substituents selected from halogeno, cyano, trifluoromethyl,(1-4C)alkyl and (1-4C)alkoxy;

(s) Q is a heterocyclic moiety containing up to 2 heteroatoms selectedfrom benzofuranyl, quinolyl, tetrahydroquinolyl, isoquinolyl,quinoxalinyl, quinazolinyl, cinnolinyl, indolyl, benzimidazolyl,indazolyl, benzoxazolyl, benzothiazolyl, dibenzofuranyl anddibenzothienyl, and Q optionally bears 1 or 2 substituents selected fromhalogeno, cyano, trifluoromethyl, (1-4C) alkyl and (1-4C)alkoxy;

(t) Q is a heterocyclic moiety containing up to 4 heteroatoms selectedfrom furyl, thienyl, pyridyl, pyrimidinyl, pyrrolyl, pyrrolidinyl,imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl,1,2,3-triazolyl, 1,2,4-triazolyl, oxadiazolyl, thiadiazolyl andtetrazolyl, and Q optionally bears 1 or 2 substituents selected fromhalogeno, cyano, carboxy, CONR⁵ R⁶, (1-4C)alkoxycarbonyl, (1-4C)alkyl,(1-4C)alkoxy;

(u) Q is a heterocyclic moiety containing up to 2 heteroatoms selectedfrom thienyl, pyridyl, pyrimidinyl, imidazolyl, pyrazolyl, oxazolyl andthiazolyl, and Q optionally bears 1 or 2 substituents selected fromhalogeno, (1-4C)alkyl, (1-4C)alkoxy, phenyl, heteroaryl, phenoxy,phenylthio, phenylsulphinyl, phenylsulphonyl, heteroaryloxy,heteroarylthio, heteroarylsulphinyl, heteroarylsulphonyl, benzyl andbenzoyl, wherein the heteroaryl substituent or the heteroaryl group in aheteroaryl-containing substituent is selected from thienyl, pyridyl,pyrimidinyl, pyrazolyl, oxazolyl and thiazolyl, and wherein said phenyl,phenyl-containing, heteroaryl or heteroaryl-containing substituentoptionally bears 1 or 2 substituents selected from halogeno, (1-4C)alkyland (1-4C)alkoxy; or

(v) Q is a heterocyclic moiety containing up to 2 heteroatoms selectedfrom thienyl, pyridyl, oxazolyl and thiazolyl, and Q bears a substituentselected from phenyl, thienyl, pyridyl, pyrimidinyl, oxazolyl andthiazolyl, which substituent optionally bears 1 or 2 substituentsselected from halogeno, (1-4C)alkyl and (1-4C) alkoxy, and Q optionallybears a further substituent selected from halogeno and (1-4C)alkyl; or apharmaceutically-acceptable salt thereof.

A preferred compound of the invention is an aminoheterocyclic derivativeof formula I,

wherein each of G¹ and G² is CH, G¹ is CH and G² is N, or G¹ is N and G²is CH;

m is 0;

L¹ is ethylene, T¹ is CH or N, and R² and R³ together form an ethylenegroup;

R⁴ is a group of formula CONR⁷ (CH₂)_(n) S(O)_(p) R⁸ or CONH(CH₂)_(q)NR⁹ R¹⁰ ;

X¹ is a group of the formula S(O)_(p) ; and

Q is phenyl, styryl, 4-biphenylyl or 2-naphthyl which optionally bears 1or 2 substituents selected from fluoro, chloro, bromo, trifluoromethyl,methyl and methoxy; or a pharmaceutically-acceptable salt thereof.

A further preferred compound of the invention is an aminoheterocyclicderivative of formula I,

wherein each of G¹ and G² is CH;

m is 0;

L¹ is ethylene, T¹ is N, and R² and R³ together form an ethylene group;

R⁴ is a group of formula CONR⁷ (CH₂)_(n) S(O)_(p) R⁸ or CONH(CH₂)_(q)NR⁹ R¹⁰ ;

X¹ is a group of the formula SO₂ ; and

Q is 2-naphthyl, styryl or 4-biphenylyl which optionally bears 1 or 2substituents selected from fluoro, chloro and bromo; or apharmaceutically-acceptable salt thereof.

Specific preferred compounds of the invention are the followingaminoheterocyclic derivatives of formula I:

4-(6-bromonaphth-2-ylsulphonyl)-2-[N-(ethylthioethyl)carbamoyl]-1-[1-(4-pyridyl)piperidin-4-ylcarbonyl]piperazine;

4-(6-bromonaphth-2-ylsulphonyl)-2-thiomorpholinocarbonyl-1-[1-(4-pyridyl)piperidin-4-ylcarbonyl]piperazine;

4-(6-bromonaphth-2-ylsulphonyl)-2-(thiomorpholino-1,1-dioxide)carbonyl-1-[1-(4-pyridyl)piperidin-4-ylcarbonyl]piperazine;

4-(6-bromonaphth-2-ylsulphonyl)-2-(3-tetrahydrothiophene1,1-dioxide)carbomoyl-1-[1-(4-pyridyl)piperidin-4-ylcarbonyl]piperazine;and

4-(6-bromonaphth-2-ylsulphonyl)-2-[N-(2-dimethylaminoethyl)carbamoyl]-1-[1-(4-pyridyl)piperidin-4-ylcarbonyl]piperazine;

or a pharmaceutically-acceptable salt of any one thereof.

An aminoheterocyclic derivative of formula I, orpharmaceutically-acceptable salt thereof, may be prepared by any processknown to be applicable to the preparation of structurally-relatedcompounds. Such procedures are provided as a further feature of theinvention and are illustrated by the following representative process inwhich, unless otherwise stated G¹, G², m, R¹, R², L¹, T¹, R³, R⁴, X¹ andQ have any of the meanings defined hereinbefore, provided that whenthere is an amino, alkylamino, hydroxy or carboxy group in R¹, L¹, R²,R³, R⁴ or Q then any such group is protected by a conventionalprotecting group which may be removed when so desired by conventionalmeans.

The compounds required as starting materials for the processes describedbelow may be prepared using standard procedures of organic chemistry.The preparation of such starting materials is illustrated within theaccompanying Examples; alternatively analogous procedures to thoseillustrated may be employed by applying no more than the ordinary skillof an organic chemist:

a) For those compounds in which R⁴ represents CONR⁷ (CH₂)_(n) S(O)_(p)R⁸ or CONH(CH₂)_(q) NR⁹ R¹⁰ reaction of a correspondingaminoheterocyclic derivative in which R⁴ represents --COOH, or areactive derivative thereof, with a compound of formula IIa or IIb:

    NHR.sup.7 (CH.sub.2).sub.n S(O).sub.p R.sup.8              IIa

    NH.sub.2 (CH.sub.2).sub.q NR.sup.9 R.sup.10                IIb

A suitable reactive derivative of an aminoheterocyclic derivativecorresponding to formula I but wherein R⁴ is --COOH is, for example, anacyl halide, for example an acyl chloride formed by the reaction of theacid and an inorganic acid chloride, for example thionyl chloride; amixed anhydride, for example an anhydride formed by the reaction of theacid with a chloroformate such as isobutyl chloroformate or with anactivated ketone such as 1,1'-carbonyidiimidazole; an active ester, forexample an ester formed by the reaction of the acid and a phenol such aspentafluorophenol, an ester such as pentafluorophenyl trifluoroacetateor an alcohol such as N-hydroxybenzotriazole or N-hydroxysuccinimide; anacyl azide, for example an azide formed by the reaction of the acid andan azide such as diphenylphosphoryl azide; an acyl cyanide, for examplea cyanide formed by the reaction of an acid and a cyanide such asdiethylphosphoryl cyanide; or the product of the reaction of the acidand a carbodiimide such as N,N'-dicyclohexylcarbodiimide orN-(3-dimethylaminopropyl)-N'-ethylcarbodiimide.

The reaction is conveniently carried out in the presence of a suitablebase such as, for example, an alkali or alkaline earth metal carbonate,alkoxide, hydroxide or hydride, for example sodium carbonate, potassiumcarbonate, sodium ethoxide, potassium butoxide, sodium hydroxide,potassium hydroxide, sodium hydride or potassium hydride, or anorganometallic base such as an alkyl-lithium, for examplen-butyl-lithium, or a dialkylamino-lithium, for example lithiumdi-isopropylamide, or, for example, an organic amine base such as, forexample, pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine,triethylamine, morpholine or diazabicyclo[5.4.0]undec-7-ene. Thereaction is also preferably carried out in a suitable inert solvent ordiluent, for example methylene chloride, chloroform, carbontetrachloride, tetrahydrofuran, 1,2-dimethoxyethane,N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidin-2-one,dimethylsulphoxide or acetone, and at a temperature in the range, forexample, -78° to 150° C., conveniently at or near ambient temperature.

A suitable protecting group for an amino or alkylamino group is, forexample, an acyl group, for example an alkanoyl group such as acetyl, analkoxycarbonyl group, for example a methoxycarbonyl, ethoxycarbonyl ortert-butoxycarbonyl group, an arylmethoxycarbonyl group, for examplebenzyloxycarbonyl, or an aroyl group, for example benzoyl. Thedeprotection conditions for the above protecting groups necessarily varywith the choice of protecting group. Thus, for example, an acyl groupsuch as an alkanoyl or alkoxycarbonyl group or an aroyl group may beremoved for example, by hydrolysis with a suitable base such as analkali metal hydroxide, for example lithium or sodium hydroxide.Alternatively an acyl group such as a tert-butoxycarbonyl group may beremoved, for example, by treatment with a suitable acid such ashydrochloric, sulphuric or phosphoric acid or trifluoroacetic acid andan arylmethoxycarbonyl group such as a benzyloxycarbonyl group may beremoved, for example, by hydrogenation over a catalyst such aspalladium-on-carbon, or by treatment with a Lewis acid for example borontris(trifluoroacetate). A suitable alternative protecting group for aprimary amino group is, for example, a phthaloyl group which may beremoved by treatment with an alkylamine, for exampledimethylaminopropylamine, or with hydrazine.

A suitable protecting group for a hydroxy group is, for example, an acylgroup, for example an alkanoyl group such as acetyl, an aroyl group, forexample benzoyl, or an arylmethyl group, for example benzyl. Thedeprotection conditions for the above protecting groups will necessarilyvary with the choice of protecting group. Thus, for example, an acylgroup such as an alkanoyl or an aroyl group may be removed, for example,by hydrolysis with a suitable base such as an alkali metal hydroxide,for example lithium or sodium hydroxide. Alternatively an arylmethylgroup such as a benzyl group may be removed, for example, byhydrogenation over a catalyst such as palladium-on-carbon.

A suitable protecting group for a carboxy group is, for example, anesterifying group, for example a methyl or an ethyl group which may beremoved, for example, by hydrolysis with a base such as sodiumhydroxide, or for example a tert-butyl group which may be removed, forexample, by treatment with an acid, for example an organic acid such astrifluoroacetic acid, or for example a benzyl group which may beremoved, for example, by hydrogenation over a catalyst such as palladiumon carbon.

Starting Materials

i. The corresponding compounds in which R⁴ represents COOH may beprepared by the hydrolysis of a corresponding compound in which R⁴represents a (1-4C)alkoxycarbonyl group.

The hydrolysis reaction may conveniently be carried out in aconventional manner using, for example, acidic or basic catalysis. Asuitable acid for the acidic hydrolysis of an ester group is, forexample, an inorganic acid such as hydrochloric or sulphuric acid. Asuitable base for the basic hydrolysis of an ester group is, forexample, an alkali or alkaline earth metal hydroxide such as sodiumhydroxide or potassium hydroxide.

The reaction is conveniently performed in a suitable solvent or diluentsuch as an alcohol, for example methanol or ethanol, and at atemperature in the range, for example 0° to 120° C., conveniently in therange of 15° to 60° C.

ii. The corresponding compounds of in which R⁴ represents a(1-4C)alkoxycarbonyl group may be prepared by an analogous process tothat described in either process b) or c) below.

Reference may also be made to PCT Application 96/10022 which describesmethods for preparing compounds corresponding to formula I, for examplewherein R⁴ is COOH or (1-4C)alkoxycarbonyl.

b) For those compounds in which T¹ represents CH, reaction of acorresponding acid of formula III or a reactive derivative thereof, withan amine of formula IV. ##STR2##

Suitable reactive derivatives of the acid of formula III and reactionconditions etc are as described in a) above.

Starting Materials

i. For those compounds of formula IV in which R⁴ represents(1-4C)alkyl-Y¹, and Y¹ is other then O(CH₂)_(r) R¹³, reaction of acompound of formula V, wherein L¹ is a leaving group and P¹ is aprotecting group, with a compound of formula VI, in the presence of asuitable base, ##STR3## followed by deprotection.

Suitable groups for P¹ are as described in process a). Suitable groupsfor L¹ include chloro, mesylate and tosylate.

ii. For those compounds of formula IV in which R⁴ represents(1-4C)alkyl-Y¹ and Y¹ represents O(CH₂)_(r) R¹³ appropriate manipulationof a compound of formula VII: ##STR4## iii. Compound of formula VII maybe prepared by reaction of a compound of formula VIII, with a compoundof formula IX: ##STR5## wherein L² represents a leaving group, forexample bromo.

c) For those compounds in which T¹ represents N, reaction of acorresponding amine of formula X with an ester of formula XI: ##STR6##

Suitable groups which E¹ may represent include 2,4,5-trichlorophenyl and4-nitrophenyl. The reaction is preferably carried out in a suitableinert solvent or diluent, for example N,N-dimethylformamide, and at atemperature in the range, for example, 50° to 150° C.

Starting Materials

i. The esters of formula XI may be prepared by the reaction of a salt,for example the hydrochloride salt, of compound of formula IV with acompound of formula XII:

    E.sup.1 --OCOCl                                            XII

The reaction is preferably carried out in a suitable inert solvent ordiluent, for example methylene chloride, and at a temperature in therange, for example, 0° to 100° C., conveniently at ambient temperature.

d) For the production of those compounds of the formula I wherein L¹,R², R³, R⁴, or Q bears a CONR⁵ R⁶ group, the reaction of a compound ofthe formula I wherein L¹, R², R³, R⁴ or Q bears a carboxy group, or areactive derivative thereof as defined hereinbefore, with ammonia or anappropriate alkylamine or dialkylamine.

The reaction is conveniently performed in a suitable inert solvent ordiluent as defined hereinbefore and at a temperature in the range, forexample, 0° to 120° C., conveniently in the range 15° to 60°.

e) For the production of those compounds of the formula I wherein X¹ isa group of formula SO or S₂, wherein R⁴ contains a SO or S₂ group, orwherein Q bears a (1-4C)alkylsulphinyl, (1-4C) alkylsulphonyl,phenylsulphinyl, phenylsulphonyl, heteroarylsulphinyl orheteroarylsulphonyl group, the oxidation of the corresponding compoundof the formula I which contains a thio group.

A suitable oxidising agent is, for example, any agent known in the artfor the oxidation of thio to sulphinyl and/or sulphonyl, for example,hydrogen peroxide, a peracid (such as 3-chloroperoxybenzoic orperoxyacetic acid), an alkali metal peroxysulphate (such as potassiumperoxymonosulphate), chromium trioxide or gaseous oxygen in the presenceof platinum. The oxidation is generally carried out under as mildconditions as possible and with the required stoichiometric amount ofoxidising agent in order to reduce the risk of over oxidation and damageto other functional groups. In general the reaction is carried out in asuitable solvent or diluent such as methylene chloride, chloroform,acetone, tetrahydrofuran or tert-butyl methyl ether and at atemperature, for example, at or near ambient temperature, that is in therange 15 to 35° C. When a compound carrying a sulphinyl group isrequired a milder oxidising agent may also be used, for example sodiumor potassium metaperiodate, conveniently in a polar solvent such asacetic acid or ethanol. It will be appreciated that when a compound ofthe formula I containing a sulphonyl group is required, it may beobtained by oxidation of the corresponding sulphinyl compound as well asof the corresponding thio compound.

When a pharmaceutically-acceptable salt of a compound of formula I isrequired, it may be obtained, for example, by reaction of said compoundwith a suitable acid or base using a conventional procedure.

When an optically active form of a compound of formula I is required, itmay be obtained, for example, by carrying out one of the aforesaidprocedures using an optically active starting material or by resolutionof a racemic form of said compound using a conventional procedure.

As stated previously, the compounds of formula I are inhibitors of theenzyme Factor Xa. The effects of this inhibition may be demonstratedusing one or more of the standard procedures set out hereinafter:

a) Measurement of Factor Xa Inhibition

An in vitro assay system was carried out based on the method of Kettneret al., J. Biol. Chem., 1990, 265, 18289-18297, whereby variousconcentrations of a test compound were dissolved in a pH7.5 buffercontaining 0.5% of a polyethylene glycol (PEG 6000) and incubated at 37°C. with human Factor Xa (0.001 Units/ml, 0.3 ml) for 15 minutes. Thechromogenic substrate S-2765 (KabiVitum AB, 20 μM) was added and themixture was incubated at 37° C. for 20 minutes whilst the absorbance at405 nm was measured. The maximum reaction velocity (Vmax) was determinedand compared with that of a control sample containing no test compound.Inhibitor potency was expressed as an IC₅₀ value.

b) Measurement of Thrombin Inhibition

The procedure of method a) was repeated except that human thrombin(0.005 Units/ml) and the chromogenic substrate S-2238 (KabiVitum AB, 7μM) were employed.

c) Measurement of Anticoagulant Activity

An in vitro assay whereby human, rat or rabbit venous blood wascollected and added directly to a sodium citrate solution (3.2 g/100 ml,9 parts blood to 1 part citrate solution). Blood plasma was prepared bycentrifugation (1000 g, 15 minutes) and stored at 2-4° C. Conventionalprothrombin time (PT) tests were carried out in the presence of variousconcentrations of a test compound and the concentration of test compoundrequired to double the clotting time, hereinafter referred to as CT2,was determined. In the PT test, the test compound and blood plasma wereincubated at 37° C. for 10 minutes. Tissue thromboplastin with calcium(Sigma Limited, Poole, England) was added. Fibrin formation and the timerequired for a clot to form were determined.

d) An ex vivo Assay of Anticoagulant Activity

The test compound was administered intravenously or orally to a group ofAlderley Park Wistar rats. At various times thereafter animals wereanaesthetised, blood was collected and PT coagulation assays analogousto those described hereinbefore were conducted. In addition the plasmaconcentration of compounds is determined by comparison with theanti-Factor Xa activity of a standard compound.

e) An in vivo Measurement of Antithrombotic Activity

Thrombus formation was induced using an analogous method to thatdescribed by Vogel et al., Thromb. Research, 1989, 54, 399-410. A groupof Alderley Park Wistar rats was anaesthetised and surgery was performedto expose the vena cava. Collateral veins were ligated and two loosesutures were located, 0.7 cm apart, round the inferior vena cava. Testcompound was administered intravenously or orally. At an appropriatetime thereafter tissue thromboplastin (30 μ/kg) was administered via thejugular vein and, after 10 seconds, the two sutures were tightened toinduce stasis within the ligated portion of vena cava. After 10 minutesthe ligated tissue was excised and the thrombus therein was isolated,blotted and weighed.

f) An in vivo Measurement of Antithrombotic Activity

Using a method similar to that of Smith J R et al Br. J Pharmacol. 1982,77: 29-38, fasted male Alderley Park rats (360-410 g) are pre-dosed atvarious times by oral (5 ml/kg) or subcutaneous (1 ml/kg) routes beforebeing anaesthetised with Intraval (120 mg/kg i.p.). The left jugularvein and the right carotid artery are exposed and cannulated with apolypropylene catheters 12 cm in length. An arterio-venous shunt iscompleted by connecting the two catheters with a 6 cm length of tubing(i.d. 0.3 cm) which contains a 5 cm length of pre-weighed cotton. Alltubes were filled with saline prior to the establishment of the circuit.Clamps are removed from the catheters and blood is allowed to flowthrough the polypropylene tubing for 20 mins. During this time theeffect of the test compound on template bleeding time is assessed. Theshunt is then closed and the thrombus which has developed on the cottonthread is removed, blotted dry and weighed. Blood samples are also takenat this point by cardiac puncture into 3.2% tri-sodium citrate, plasmais prepared by centrifugation (5 mins 20000 g) and frozen for subsequentprothrombin time and drug level determinations.

The plasma concentration of the compound is extrapolated from thestandard curve and expressed in Anti-Factor Xa units. Thrombus weight ismeasured following dosing of vehicle or test compound. Data is expressedas % inhibition of thrombus formation in the presence of compound whencompared to thrombus weight from a group of control animals.

Although the pharmacological potencies of the compounds of formula Ivary with structural changes as expected, in general compounds of theformula I possess activity at the following concentrations or doses inat least one of the above tests a) to c):

test a): IC₅₀ (Factor Xa) in the range, for example, 0.001-25 μM;

test b): IC₅₀ (thrombin), for example, greater than 10 μM;

test c): CT2 (PT) in the range, for example, 0.1-50 μM.

By way of example, the compound of Example 1 as disclosed hereinafterhas an IC₅₀ of 0.004 μM against Factor Xa in test a), an IC₅₀ of greaterthan 5 μM against thrombin in test b) and a CT2(PT) of 1 μm in test c).

According to a further feature of the invention there is provided apharmaceutical composition which comprises an aminoheterocyclicderivative of formula I, or a pharmaceutically-acceptable salt thereof,in association with a pharmaceutically-acceptable diluent or carrier.

The composition may be in a form suitable for oral use, for example atablet, capsule, aqueous or oily solution, suspension or emulsion; fortopical use, for example a cream, ointment, gel or aqueous or oilysolution or suspension; for nasal use, for example a snuff, nasal sprayor nasal drops; for vaginal or rectal use, for example a suppository;for administration by inhalation, for example as a finely divided powdersuch as a dry powder, a microcrystalline form or a liquid aerosol; forsub-lingual or buccal use, for example a tablet or capsule; or forparenteral use (including intravenous, subcutaneous, intramuscular,intravascular or infusion), for example a sterile aqueous or oilysolution or suspension. In general the above compositions may beprepared in a conventional manner using conventional excipients.

The amount of active ingredient (that is an aminoheterocyclic derivativeof the formula I, or a pharmaceutically-acceptable salt thereof) that iscombined with one or more excipients to produce a single dosage formwill necessarily vary depending upon the host treated and the particularroute of administration. For example, a formulation intended for oraladministration to humans will generally contain, for example, from 0.5mg to 2 g of active agent compounded with an appropriate and convenientamount of excipients which may vary from about 5 to about 98 percent byweight of the total composition. Dosage unit forms will generallycontain about 1 mg to about 500 mg of an active ingredient.

According to a further feature of the invention there is provided anaminoheterocyclic derivative of formula I, or apharmnaceutically-acceptable salt thereof, for use in a method oftreatment of the human or animal body by therapy.

The invention also includes the use of such an active ingredient in theproduction of a medicament for use in:

(i) producing a Factor Xa inhibitory effect;

(ii) producing an anticoagulant effect;

(iii) producing an antithrombotic effect;

(iv) treating a Factor Xa mediated disease or medical condition;

(v) treating a thrombosis mediated disease or medical condition;

(vi) treating coagulation disorders; and/or

(vii) treating thrombosis or embolism involving Factor Xa mediatedcoagulation.

The invention also includes a method of producing an effect as definedhereinbefore or treating a disease or disorder as defined hereinbeforewhich comprises administering to a warm-blooded animal requiring suchtreatment an effective amount of an active ingredient as definedhereinbefore.

The size of the dose for therapeutic or prophylactic purposes of acompound of formula I will naturally vary according to the nature andseverity of the medical condition, the age and sex of the animal orpatient being treated and the route of administration, according to wellknown principles of medicine. As mentioned above, compounds of theformula I are useful in the treatment or prevention of a variety ofmedical disorders where anticoagulant therapy is indicated. In using acompound of the formula I for such a purpose, it will generally beadministered so that a daily dose in the range, for example, 0.5 to 500mg/kg body weight is received, given if required in divided doses. Ingeneral lower doses will be administered when a parenteral route isemployed, for example a dose for intravenous administration in therange, for example, 0.5 to 50 mg/kg body weight will generally be used.For preferred and especially preferred compounds of the invention, ingeneral, lower doses will be employed, for example a daily dose in therange, for example, 0.5 to 10 mg/kg body weight.

Although the compounds of formula I are primarily of value astherapeutic or prophylactic agents for use in warm-blooded animalsincluding man, they are also useful whenever it is required to producean anticoagulant effect, for example during the ex-vivo storage of wholeblood or in the development of biological tests for compounds havinganticoagulant properties.

The compounds of the invention may be administered as a sole therapy orthey may be administered in conjunction with other pharmacologicallyactive agents such as a thrombolytic agent, for example tissueplasminogen activator or derivatives thereof or streptokinase. Thecompounds of the invention may also be administered with, for example, aknown platelet aggregation inhibitor (for example aspirin, a thromboxaneantagonist or a thromboxane synthase inhibitor), a known hypolipidaemicagent or a known anti-hypertensive agent.

The invention will now be illustrated in the following Examples inwhich, unless otherwise stated:

i. evaporations were carried out by rotary evaporation in vacuo andwork-up procedures were carried out after removal of residual solids byfiltration;

ii. operations were carried out at room temperature, that is in therange 18-25° C. and under an atmosphere of an inert gas such as argon;

iii. column chromatography (by the flash procedure) and medium pressureliquid chromatography (MPLC) were generally performed on Merck Kieselgelsilica (Art. 9385) or Merck Lichroprep RP-18 (Art. 9303) reversed-phasesilica obtained from E. Merck, Darmstadt, Germany; alternatively highpressure liquid chromatography (HPLC) was performed on a Dynamax C-18 60Å preparative reversed-phase column;

iv. yields are given for illustration only and are not necessarily themaximum attainable;

v. the end-products of the formula I have satisfactory microanalyses andtheir structures were confirmed by nuclear magnetic resonance (NMR) andmass spectral techniques; unless otherwise stated, CD₃ SOCD₃ solutionsof the end-products of the formula I were used for the determination ofNMR spectral data, chemical shift values were measured on the deltascale; the following abbreviations have been used: s, singlet; d,doublet; t, triplet; q, quartet; m, multiplet; b, broad;

vi. intermediates were not generally fully characterised and purity wasassessed by thin layer chromatographic, infra-red (IR) or NMR analysis;

vii. melting points were determined using a Mettler SP62 automaticmelting point apparatus or an oil-bath apparatus; melting points for theend-products of the formula I were generally determined aftercrystallisation from a conventional organic solvent such as ethanol,methanol, acetone, ether or hexane, alone or in admixture; and

viii. the following abbreviations have been used:

    ______________________________________                                        DMF              N,N-dimethylformamide;                                       THF              tetrahydrofuran;                                             DMSO             dimethylsulphoxide.                                          ______________________________________                                    

EXAMPLE 14-(6-Bromonaphth-2-ylsulphonyl)-2-[N-(2-(ethylthio)ethyl)carbamoyl]-[1-1-(4-pyridyl)piperidin-4-ylcarbonyl]piperazine

To a suspension of4-(6-bromonaphth-2-ylsulphonyl)-2-carboxy-1-[1-(4-pyridyl)piperidin-4-ylcarbonyl]piperazine(282 mg) in DMF (4 ml), was addedN-(3-dimethylaminopropyl)-N-ethylcarbodiimide (184 mg) and1-hydroxybenzotriazole (78 mg), followed by a solution of2-(ethylthio)ethylamine (252 mg) in DMF (1 ml). The resulting mixturewas stirred at room temperature for 18 hours. The mixture waspartitioned between dichloromethane and water. The organic extracts weredried (MgSO₄) and evaporated to a gum, which was purified bychromatography on silica, eluting with increasing polar mixtures ofmethanol and dichloromethane (up to 13% methanol). There was thusobtained the title compound as a glass (141 mg, 44%).

NMR Spectrum: 1.2 (t, 3H), 1.5-1.8 (m, 4H), 2.4-3.05 (m, 9H), 3.15-3.25(m, 2H), 3.35-3.5 (m, 1H), 3.6-3.7 (m, 1), 3.75-3.85 (m, 2H), 4.0-4.2(m, 2H), 4.8-4.9 (m, 1H), 6.75 (d, 2H), 7.5-7.6 (m, 1H), 7.75-7.8 (m,2H), 8.05-8.15 (m, 4H), 8.3 (d, 1H), 8.4 (d, 1H).

Elemental Analysis: Found C, 48.5; H, 4.85; N, 9.4; C₃₀ H₃₆ BrN₅ O₄ S₂0.1 SiO₂ requires; C, 48.8; H, 5.1; N, 9.4%

The4-(6-bromonaphth-2-ylsulphonyl)-2-carboxy-1-[1-(4-pyridyl)piperidin-4-ylcarbonyl]piperazineused as starting material was obtained as follows:

Step A

To a solution of ethyl 1-benzyl piperazine-2-carboxylate (E.Jucker,Helv.Chim.Acta (1962), 45, 2383) (6.14 g) in methylene chloride (100 ml)was added triethylamine (10.8 ml) followed by a solution of6-bromo-2-naphthylsulphonyl chloride (8.4 g) in methylene chloride (50ml) and the mixture was stirred for 18 hours. The mixture waspartitioned between methylene chloride and water. The organic phase wasdried (MgSO₄) and evaporated. The residue was purified by columnchromatography using a 1:4 mixture of ethyl acetate and hexane aseluent. There was thus obtained ethyl1-benzyl-4-(6-bromo-2-naphthylsulphonyl)piperazine-2-carboxylate as aglassy solid (10.8 g).

NMR Spectrum: 1.2 (t, 3H), 2.4-2.65 (m, 2H), 2.8 (dd, 1H), 3.0-3.1 (m,1H), 3.5-3.85 (m, 4H), 4.05-4.2 (m, 2H), 7.1-7.3 (m, 5H), 7.75-7.85 (m,2H), 8.1-8.2 (m, 2H), 8.4 (d, 1H), 8.45 (d, 1H).

Step B

1-Chloroethylchloroformate (5.55 ml) was added to a solution of ethyl1-benzyl-4-(6-bromo-2-naphthylsulphonyl)piperazine-2-carboxylate (10.5g) in 1,2-dichloroethane (125 ml) and the mixture was refluxed for 24hours. The mixture was evaporated and the residue was titurated withhexane. Methanol (100 ml) was added to the resultant gum and the mixturewas refluxed for 1.5 hours. The mixture was evaporated and the residuepartitioned between methylene chloride and water. The organic phase wasdried (MgSO₄) and evaporated. The residue was purified by chromatographyusing increasing polar mixtures of methanol and methylene chloride aseluent. There was thus obtainedethyl-1-(6-bromo-2-naphthylsulphonyl)piperazine-3-carboxylate as a gum(7.95 g).

NMR Spectrum: 1.2 (t, 3H), 2.65-3.1 (m, 6H), 3.3-3.4 (m, 1H), 3.45-3.55(m, 1H), 4.1 (q, 1H), 7.8-7.85 (m, 2H), 8.1-8.25 (m, 2H), 8.4 (d,1H).

Step C

To a solution ofethyl-1-(6-bromo-2-naphthylsulphonyl)piperazine-3-carboxylate (7.94 g)in methylene chloride (80 ml), cooled to 5° C. was added sodium hydrogencarbonate (15.6 g) followed by a solution of1-(4-pyridyl)piperidine4-carbonyl chloride (4.6 g) in methylene chloride(20 ml). The resulting mixture was stirred at room temperature for 18hours. The mixture was partitioned between methylene chloride and water.The organic extracts were dried (MgSO₄) and evaporated. The residue waspurified by chromatography using increasing polar mixtures of methanoland methylene chloride as eluent. There was thus obtained2-ethoxycarbonyl4-(6-bromo-2-naphthylsulphonyl)-1-[1-(4-pyridyl)piperidin-4-ylcarbonyl]piperazineas a glass (5.48 g).

NMR Spectrum: 1.2 (t, 3H), 1.5-1.8 (m, 4H), 2.45-2.6 (m, 1H), 2.7-3.05(m, 5H), 3.65-3.85 (m, 3H), 4.05-4.25 (m, 4H), 5.05-5.1 (m, 1H), 6.7 (d,2H), 7.75-7.8 (m, 2H), 8.05-8.15 (m, 4H), 8.3 (d, 1H), 8.45(d, 1H).

Elemental Analysis: Found: C, 54.2;H, 5.2;N, 9.0; C₂₈, H₃₁, BrN₄ O₅ Srequires: C, 54.6; H, 5.1; N, 9.1%

Step D

To a solution of2-ethoxycarbonyl-4-(6-bromo-2-naphthylsulphonyl)-1-[1-(4-pyridyl)piperidin-4-ylcarbonyl]piperazine(3.30g) in methanol (60 ml) was added 2N NaOH (10.7 ml). The mixture waswarmed to 35° C. and stirred for 30 minutes. The mixture was evaporatedto dryness. The resulting solid was dissolved in water and acidifiedwith acetic acid. The precipitate was filtered and washed with water.There was thus obtained2-carboxy-4-(6-bromo-2-naphthylsulphonyl)-1-[1-(4-pyridyl)piperidin-4-ylcarbonyl]piperazine(2.92 g) m.p. 216-222° C. (dec).

NMR Spectrum: 1.5-1.8 (m, 4H), 2.45-2.55 (m, 1H), 2.7 (dd, 1H), 2.8-3.05(m, 3H), 3.15-3.35 (bm, 1H), 3.6-4.25 (m, 5H), 4.95-5.0 (m, 1H), 6.7 (d,2H), 7.7-7.8 (m, 2H), 8.05-8.15 (m, 4H), 8.3 (d, 1H), 8.4 (d, 1H).

Elemental Analysis: Found: C, 52.4;H, 4.8;N, 9.3; C₂₆ H₂₇ BrN₄ O₅S.0.5H₂ O requires C, 52.35; H, 4.7; N, 9.4%

EXAMPLE 24-(6-Bromonaphth-2-ylsulphonyl)-2-thiomorpholinocarbonyl-1[-1-(4-pyridyl)piperidin-4-ylcarbonyl]piperazine

The procedure of Example 1 was repeated using thiomorpholine to give thetitle compound as a glass (59%), m.p. 250-258° C.;

NMR Spectrum: 1.5-1.8 (m, 4H), 2.55-2.6 (m, 4H), 2.7-3.05 (m, 5H),3.6-3.85 (m, 9H), 3.95-4.05 (m, 1H), 5.2-5.25 (m, 1H), 6.7 (d, 2H),7.75-7.85 (m, 2H), 8.1-8.15 (m, 4H), 8.3 (d, 1H), 8.45 (d, 1H).

Elemental Analysis: Found C, 52.6; H, 4.9; N, 10.4; C₃₀ H₃₄ BrN₅ O₄S₂.0.5H₂ O requires C, 52.8; H, 5.1; N, 10.3%

EXAMPLE 34-(6-Bromonaphth-2-ylsulphony)-2-(thiomorpholino-1,1-dioxide)carbonyl-1-[1-(4-pyridyl)piperidin-4-ylcarbonyl]piperazine

The procedure of Example 1 was repeated using thiomorpholine-1,1-dioxideto give the title compound as a glass (54%).

NMR Spectrum: 1.5-1.8 (m, 4H), 2.8-3.1 (m, 9H), 3.55-4.0 (m, 10H),5.2-5.25 (m, 1H), 6.7-6.75 (m, 2H), 7.75-7.85 (m, 2H), 8.05-8.15 (m,4H), 8.3 (d, 1H), 8.45(d, 1H).

Elemental Analysis: Found C, 49.9; H, 4.9; N, 9.7; S, 8.4; C₃₀ H₃₄ BrN₅O₆ S₂.H₂ O requires: C, 49.9; H, 5.0; N, 9.7; S, 8.9%.

EXAMPLE 44-(6-Bromonaphth-2-ylsulphonyl)-2-(3-tetrahydrothiophene-1,1-dioxide)carbamoyl-1-[1-(4-pyridyl)piperidin-4-ylcarbonyl]piperazine

The procedure of Example 1 was repeated using3-amino-tetrahydrothiophene-1,1-dioxide to give the title compound as aglass (79%)

NMR Spectrum: 1.5-1.8 (m, 4H), 2.0-2.15 (m, 1H), 2.25-2.45 (m, 1H),2.6-3.35 (m, 9H), 3.4-3.55 (m, 1H), 3.6-3.7 (m, 1H), 3.75-3.9 (m, 2H),4.0-4.15 (m, 2H), 4.35-4.5 (m, 1H), 4,8-4.9 (m, 1H), 6.75 (d, 2H),7.7-7.8 (m, 2H), 7.95 (d, 1H), 8.05-8.15 (m, 4H), 8.3 (d, 1H), 8.4 (d,1H).

Elemental Analysis: Found C, 49.1; H, 4.9; N, 9.5, S, 8.9; C₃₀ H₃₄ BrN₅O₆ S₂.1.5H₂ O requires C, 49.25; H, 5.05; N, 9.6; S, 8.8%

EXAMPLE 54-(6-Bromonaphth-2-ylsulphonyl)-2-[N-(2-dimethylaminoethyl)carbamoyl]-1-[1-(4-pyridyl)piperidin-4-ylcarbonyl]piperazine

The procedure of Example 1 was repeated using 2-dimethylaminoethylamineto give the title compound as a glass (30%).

NMR Spectrum: (CD₃ SOCD₃ and CD₃ COOD) 1.6-1.8 (m, 4H), 2.8 (s, 6H),3.0-3.2 (m, 4H), 3.25-3.75 (m, 8H), 3.95-4.1 (m, 3H), 4.2-4.3 (m, 1H),4.95-5.0 (m, 1H), 7.0 (d, 2H), 7.7-7.8 (m, 2H), 8.0-8.1 (m, 4H), 8.25(d, 1H), 8.4 (d, 1H).

Elemental Analysis: Found: C, 53.8; H, 5.6; N, 12.1; C₃₀ H₃₇ BrN₆ O₄S.0.75H₂ O requires C, 53.7; H, 5.75; N, 12.5%

EXAMPLE 6

The following illustrate representative pharmaceutical dosage formscontaining the compound of formula I, or a pharmaceutically-acceptablesalt thereof (hereafter compound X), for therapeutic or prophylactic usein humans:

    ______________________________________                                        (a) Tablet 1             mg/tablet                                            ______________________________________                                            Compound X           100                                                      Lactose Ph.Eur.      182.75                                                   Croscarmellose sodium                                                                              12.0                                                     Maize starch paste (5% w/v paste)                                                                  2.25                                                     Magnesium stearate   3.0                                                  ______________________________________                                        (b) Tablet II            mg/tablet                                            ______________________________________                                            Compound X           50                                                       Lactose Ph.Eur.      223.75                                                   Croscarmellose sodium                                                                              6.0                                                      Maize starch         15.0                                                     Polyvinylpyrrolidone (5% w/v paste)                                                                2.25                                                     Magnesium stearate   3.0                                                  ______________________________________                                        (c) Tablet III           mg/tablet                                            ______________________________________                                            Compound X           1.0                                                      Lactose Ph.Eur.      93.25                                                    Croscarmellose sodium                                                                              4.0                                                      Maize starch paste (5% w/v paste)                                                                  0.75                                                     Magnesium stearate   1.0                                                  ______________________________________                                        (d) Capsule              mg/capsule                                           ______________________________________                                            Compound X           10                                                       Lactose Ph.Eur.      488.5                                                    Magnesium stearate   1.5                                                  ______________________________________                                        (e) Injection I          (50 mg/ml)                                           ______________________________________                                            Compound X           5.0% w/v                                                 1M Sodium hydroxide solution                                                                       15.0% w/v                                                0.1M Hydrochloric acid                                                        (to adjust pH to 7.6)                                                         Polyethylene glycol 400                                                                            4.5% w/v                                                 Water for injection to 100%                                               ______________________________________                                        (f) Injection II         10 mg/ml)                                            ______________________________________                                            Compound X           1.0% w/v                                                 Sodium phosphate BP  3.6% w/v                                                 0.1M Sodium hydroxide solution                                                                     15.0% w/v                                                Water for injection to 100%                                               ______________________________________                                        (g) Injection III        (1 mg/ml,buffered to pH6)                            ______________________________________                                            Compound X           0.1% w/v                                                 Sodium phosphate BP  2.26% w/v                                                Citric acid          0.38% w/v                                                Polyethylene glycol 400                                                                            3.5% w/v                                                 Water for injection to 100%                                               ______________________________________                                         Note                                                                          The above formulations may be obtained by conventional procedures well        known in the pharmaceutical art. The tablets (a)-(c) may be enteric coate     by conventional means, for example to provide a coating of cellulose          acetate phthalate.                                                       

I claim:
 1. A compound of the formula I: ##STR7## wherein G¹ and G²independently represent CH or N; m is 0, 1 or 2;R¹ is halogeno,trifluoromethyl, trifluoromethoxy, cyano, NR⁵ R⁶, hydroxy, nitro,(1-4C)alkyl or (1-4C)alkoxy; T¹ is CH or N; L¹ is (1-4C)alkylene,(3-6C)cycloalkane-1,2-diyl or (1-3C)alkylene-carbonyl; R² is hydrogen or(1-4C)alkyl and R³ is hydrogen or (1-4C)alkyl, or R² and R³ togetherform a (1-4C)alkylene or methylenecarbonyl group, wherein 1 or 2methylene groups within L¹ or the ring formed when R² and R³ are linkedoptionally bears 1 or 2 substituents selected from carboxy, CONR⁵ R⁶,(1-4C)alkyl, (1-4C)alkoxycarbonyl, pyrrolidin-1-ylcarbonyl,piperidinocarbonyl, morpholinocarbonyl, piperazin-1-yl, carbonyl,4-(1-4C)alkylpiperazin-1-ylcarbonyl, hydroxy-(1-4C)alkyl,(1-4C)alkoxy-(1-4C)alkyl, carboxy-(1-4C)alkyl,(1-4C)alkoxycarbonyl-(1-4C)alkyl, CONR⁵ R⁶ (1-4C)alkyl,pyrrolidin-1-ylcarbonyl-(1-4C)alkyl, piperidino-(1-4C)alkyl,morpholino-(1-4C)alkyl, piperazin-1-yl-(1-4C)alkyl and4-(1-4C)alkylpiperazin-1-yl-(1-4C)alkyl, and wherein any heterocyclicgroup in said substituent optionally bears 1 or 2 (1-4C)alkylsubstituents; R⁴ is CONR⁷ (CH₂)_(n) S(O)_(p) R⁸, CONH(CH₂)_(q) NR⁹ R¹⁰,or the group (1-4C)alkyl-Y¹ ; wherein n represents an integer 0 to 4; prepresents 0, 1 or 2; q represents an integer 2 to 4; R⁷ representshydrogen; R⁸ represents (1-4C)alkyl, phenyl or (1-4C) alkylphenyl, or R⁷and R⁸ together form a (1-4C)alkylene group; R⁹ and R¹⁰ independentlyrepresent hydrogen, (1-4C)alkyl, phenyl, (1-4C)alkylphenyl, S(O)_(p) R⁸,COR¹¹ or a 5- or 6-membered monocyclic heteroaryl ring having up to 3heteroatoms selected from nitrogen, oxygen and sulphur; R¹¹ representshydrogen, (1-4C)alkyl, phenyl or (1-4C)alkylphenyl; Y¹ representsS(O)_(p) R⁸, NHS(O)₂ R⁸, NHCOR¹², O(CH₂)_(r) R³, pyrrolidin-1-yl,piperidino, morpholino, thiamorpholino, 1-oxothiamorpholino,1,1-dioxothiamorpholino or piperazin-1-yl, R¹² represents (1-4C)alkyl,phenyl or (1-4C)alkylphenyl; r represents an integer 1 to 4; when rrepresents an integer 2 to 4, R¹³ represents hydroxy, (1-4C)alkoxy,carboxy, (1-4C)alkoxycarbonyl, S(O)_(p) R⁸ or NR⁵ R⁶ ; and when rrepresents 1, R¹³ represents carboxy or (1-4C)alkoxycarbonyl; whereinany heterocyclic group within R⁴ optionally bears 1 or 2 substituentsselected from carboxy, CONR⁵ R⁶, (1-4C)alkyl and (1-4C) alkoxycarbonyl,and any phenyl group within R⁴ optionally bears 1 or 2 substituentsselected from halogeno, trifluoromethyl, cyano, (1-4C) alkyl and(1-4C)alkoxy; X¹ is a group of the formula O, S(O)_(p), CO, COO, CONR¹⁴or CR¹⁵ R¹⁶ ; R⁵, R⁶, R¹⁴, R¹⁵ and R¹⁶ independently represent hydrogenor (1-4C)alkyl; and Q represents phenyl, naphthyl, phenyl-(1-4C)alkyl ora heterocyclic moiety having up to 4 heteroatoms selected from nitrogen,oxygen and sulphur, and Q optionally bears 1, 2 or 3 substituentsselected from halogeno, trifluoromethyl, trifluoromethoxy, cyano,hydroxy, NR⁵ R⁶, nitro, trifluoromethanesulphonyl, carboxy, CONR⁵ R⁶,(1-4C)alkyl, (1-4C)alkoxy, (1-4C)alkylS(O)_(p), (1-4C)alkoxycarbonyl,(2-4C)alkanoyl, (2-4C)alkanoylamino, hydroxy-(1-4C)alkyl,(1-4C)alkoxy-(1-C)alkyl, carboxy-(1-4C)alkyl,(1-4C)alkoxycarbonyl-(1-4C) alkyl, CONR⁵ R⁶ (1-4C)alkyl, phenyl,heteroaryl, phenoxy, phenylS(O)_(p), benzyl, benzoyl, heteroaryloxy,heteroarylS(O)_(p), wherein said heteroaryl substituent has a 5- or6-membered monocyclic heteroaryl ring having up to 3 heteroatomsselected from nitrogen, oxygen and sulphur, and wherein said phenyl,heteroaryl, phenoxy, phenylS(O)_(p), heteroaryloxy, heteroarylS(O)_(p),benzyl or benzoyl substituent optionally bears 1, 2 or 3 substituentsselected from halogeno, trifluoromethyl, cyano, hydroxy, NR⁵ R⁶, nitro,carboxy, CONR⁵ R⁶, (1-4C)alkyl, (1-4C)alkoxy, (1-4C)alkoxycarbonyl and(2-4C)alkanoylamino;or a pharmaceutically-acceptable salt thereof.
 2. Acompound according to claim 1 wherein:each of G¹ and G² is CH; or G¹ isCH and G² is N, or G¹ is N and G² is CH; m is 0; L¹ is (1-4C)alkylene,T¹ is CH or N, and R² and R³ together form a (1-4C)alkylene group, andwherein 1 or 2 methylene groups within L¹ and the ring formed when R²and R³ are linked optionally bears 1 or 2 (1-4C)alkyl substituents; R⁴is a group of formula CONR⁷ (CH₂)_(n) S(O)_(p) R⁸ or CONH(CH₂)_(q) NR⁹R¹⁰ ; X¹ is a group of the formula S(O)_(p) ; Q is phenyl, naphthyl orphenyl-(1-4C)alkyl which optionally bears 1, 2 or 3 substituentsselected from hydroxy, halogeno, cyano, trifluoromethyl, (1-4C)alkyl,(1-4C)alkoxy, phenyl, phenoxy, phenylS(O)_(p), benzyl and benzoyl, andwherein the phenyl substituent or the phenyl group in aphenyl-containing substituent optionally bears 1 or 2 substituentsselected from halogeno, (1-4C)alkyl and (1-4C)alkoxy; or Q isphenyl-(2-4C)alkenyl or phenyl-(2-4C)alkynyl which optionally bears 1, 2or 3 substituents selected from halogeno, cyano, trifluoromethyl,(1-4C)alkyl and (1-4C)alkoxy; or Q is phenyl or phenyl-(1-4C)alkyl whichbears 1 substituent selected from heteroaryl, heteroaryloxy,heteroarylthio, heteroarylsulphinyl and heteroarylsulphonyl, wherein theheteroaryl substituent or the heteroaryl group in a heteroarylsubstituent has a 5- or 6-membered monocyclic heteroaryl ring having upto 3 heteroatoms selected from nitrogen, oxygen and sulphur, and whereinsaid heteroaryl or heteroaryl substituent optionally bears 1 or 2substituents selected from halogeno, (1-4C)alkyl and (1-4C)alkoxy; or Qis a heterocyclic moiety having up to 2 heteroatoms selected frombenzofuranyl, quinolyl, tetrahydroquinolyl, isoquinolyl, quinoxalinyl,quinazolinyl, cinnolinyl, indolyl, benzimidazolyl, indazolyl,benzoxazolyl, benzothiazolyl, dibenzofuranyl and dibenzothienyl, and Qoptionally bears 1 or 2 substituents selected from halogeno, cyano,trifluoromethyl, (1-4C)alkyl and (1-4C)alkoxy; or Q is a heterocyclicmoiety having up to 4 heteroatoms selected from furyl, thienyl, pyridyl,pyrimidinyl, pyrrolyl, pyrrolidinyl, imidazolyl, pyrazolyl, oxazolyl,isoxazolyl, thiazolyl, isothiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl,oxadiazolyl, thiadiazolyl and tetrazolyl, and Q optionally bears 1 or 2substituents selected from halogeno, cyano, carboxy, CONR⁵ R⁶,(1-4C)alkoxycarbonyl, (1-4C)alkyl, (1-4C)alkoxy; or Q is a heterocyclicmoiety having up to 2 heteroatoms selected from thienyl, pyridyl,pyrimidinyl, imidazolyl, pyrazolyl, oxazolyl and thiazolyl, and Qoptionally bears 1 or 2 substituents selected from halogeno,(1-4C)alkyl, (1-4C)alkoxy, phenyl, heteroaryl, phenoxy, phenylthio,phenylsulphinyl, phenylsulphonyl, heteroaryloxy, heteroarylthio,heteroarylsulphinyl, heteroarylsulphonyl, benzyl and benzoyl, whereinthe heteroaryl substituent or the heteroaryl group in a heteroarylsubstituent is selected from thienyl, pyridyl, pyrimidinyl, pyrazolyl,oxazolyl and thiazolyl, and wherein said phenyl, phenyl substituent,heteroaryl or heteroaryl substituent optionally bears 1 or 2substituents selected from halogeno, (1-4C)alkyl and (1-4C)alkoxy;or apharmaceutically-acceptable salt thereof.
 3. A compound according toclaim 1 wherein each of G¹ and G² is CH, G¹ is CH and G² is N, or G¹ isN and G² is CH;m is 0; L¹ is ethylene, T¹ is CH or N, and R² and R³together form an ethylene group; R⁴ is a group of formula CONR⁷(CH₂)_(n) S(O)_(p) R⁸ or CONH(CH₂)_(q) NR⁹ R¹⁰ ; X¹ is a group of theformula S(O)_(p) ; and Q is phenyl, styryl, 4-biphenylyl or 2-naphthylwhich optionally bears 1 or 2 substituents selected from fluoro, chloro,bromo, trifluoromethyl, methyl and methoxy;or apharmaceutically-acceptable salt thereof.
 4. A compound according toclaim 1 wherein each of G¹ and G² is CH;m is 0; L¹ is ethylene, T¹ is N,and R² and R³ together form an ethylene group; R⁴ is a group of formulaCONR⁷ (CH₂)_(n) S(O)_(p) R⁸ or CONH(CH₂)_(q) NR⁹ R¹⁰ ; X¹ is a group ofthe formula SO₂ ; and Q is 2-naphthyl, styryl or 4-biphenylyl whichoptionally bears 1 or 2 substituents selected from fluoro, chloro andbromo;or a pharmaceutically-acceptable salt thereof.
 5. A compoundaccording to claim 1 whichis:4-(6-bromonaphth-2-ylsulphonyl)-2-[N-(ethylthioethyl)carbamoyl]-1-[1-(4-pyridyl)piperidin-4-ylcarbonyl]piperazine;4-(6-bromonaphth-2-ylsulphonyl)-2-thiomorpholinocarbonyl-1-[1-(4-pyridyl)piperidin-4-ylcarbonyl]piperazine;4-(6-bromonaphth-2-ylsulphonyl)-2-(thiomorpholino-1,1-dioxide)carbonyl-1-[1-(4-pyridyl)piperidin-4-ylcarbonyl]piperazine;4-(6-bromonaphth-2-ylsulphonyl)-2-(3-tetrahydrothiophene1,1-dioxide)carbomoyl-1-[1-(4-pyridyl)piperidin-4-ylcarbonyl]piperazine;and4-(6-bromonaphth-2-ylsulphonyl)-2-[N-(2-dimethylaminoethyl)carbamoyl]-1-[1-(4-pyridyl)piperidin-4-ylcarbonyl]piperazine;ora pharmaceutically-acceptable salt of any one thereof.
 6. Apharmaceutical composition which comprises a compound of the formula Ior a pharmaceutically acceptable salt thereof as claimed in any one ofclaims 1 to 5 and a pharmaceutically acceptable carrier.
 7. A method fortreating coronary artery or cerebro-vascular disease comprising the stepof administering a compound of the formula I, or a pharmaceuticallyacceptable salt thereof, as claimed in any one of claims 1 to
 5. 8. Aprocess for the preparation of a compound of the formula I or apharmaceutically acceptable salt thereof as claimed in claim 1, whichcomprises:a) for a preparation of those compounds in which R⁴ representsCONR⁷ (CH₂)nS(O)pR⁸ or CONH(CH₂)qNR⁹ R¹⁰, reaction of a correspondingcompound in which R⁴ represents COOH, or a reactive derivative thereof,with a compound of the formula IIa or IIb:

    NHR.sup.7 (CH.sub.2).sub.n S(O).sub.p R.sup.8              IIa

    NH.sub.2 (CH.sub.2).sub.q NR.sup.9 R.sup.10                IIb

b) for the preparation of those compounds in which T¹ represents CH,reaction of a corresponding acid of the formula III or a reactivederivative thereof with an amine of the formula IV: ##STR8## c) for thepreparation of those compounds in which T¹ represents N, reaction of acorresponding amine of the formula X with an ester of the formula XI:##STR9## d) for the production of those compounds of the formula Iwherein L¹, R², R³, R⁴ or Q bears a CONR⁵ R⁶ group, the reaction of acompound of the formula I wherein L¹, R², R³, R⁴ or Q bears a carboxygroup, or a reactive derivative thereof, with NHR⁵ R⁶ ; or e) for theproduction of those compounds of the formula I wherein X¹ is a group ofthe formula SO or SO₂, wherein R⁴ has a SO or SO₂ group wherein Q bearsa (1-4C)alkylsulphinyl, (1-4C)alkysulphonyl, phenylsulphonyl,phenylsulphinyl, heteroarylsulphinyl or heteroarylsulphonyl group, theoxidation of the corresponding compound of the formula I which has athio group; and if necessary forming a pharmaceutically acceptable salt.9. A method for producing an antithrombotic or anticoagulant effect inblood comprising the step of administering a compound of the formula I,or a pharmaceutically acceptable salt thereof, as claimed in claim 1.